In the current study, we established and validated a simple and sensitive liquid chromatography-tandem mass spectrometric method for the determination of 21-hydroxy deflazacort in nude mice plasma, and such a method w...In the current study, we established and validated a simple and sensitive liquid chromatography-tandem mass spectrometric method for the determination of 21-hydroxy deflazacort in nude mice plasma, and such a method was applied to a pharmacokinetic study. Using betamethasone as the internal standard, the plasma samples were pre-treated by precipitation with acetonitrile and then analyzed on a reversed-phase C18 column （50 mm×2 mm, 5 μm） with a mobile phase consisting of acetonitrile and 4.0 mM ammonium formate （pH was adjusted to 3.5 with formic acid （40：60, v/v））. The analyte was detected by a triple quadrupole tandem mass spectrometer using electrospray, and multiple reaction monitoring was employed to select 21-hydroxy deflazacort at m/z 400.2/124.0 and betamethasone at m/z 393.3/147.0 in the positive ion mode. The calibration curves were linear （r〉0.99） over the range of 0.5~,00 ng/mL. The intra- and inter-day precisions and accuracies were 4.5%-10.1% and -1.7%-10.7% respectively. This method was successfully applied to a preclinical administered with a single oral dose of 4 mg/kg deflazacort, and its pharmacokinetic study of deflazacort on female nude mice pharmacokinetics was characterized by a two-compartment model with first-order absorption.展开更多
A sensitive,rapid and simple liquid chromatography-tandem mass spectrometric（LC-MS/MS） method was developed and validated for the determination of letrozole（LTZ） in nude mouse plasma in the current study,which was...A sensitive,rapid and simple liquid chromatography-tandem mass spectrometric（LC-MS/MS） method was developed and validated for the determination of letrozole（LTZ） in nude mouse plasma in the current study,which was successfully applied to a pharmacokinetic study.Using anastrozole as internal standard（IS）,plasma samples went through a one-step protein precipitation with acetonitrile before determination.The analyte and IS were analyzed on a reversed-phase ZORBAX-SB-C18 column（4.6 mm×250 mm,5 μm） with an isocratic mobile phase consisting of acetonitrile and water containing 0.1% formic acid（v/v） at a flow rate of 1.0 mL/min.The analyte and IS were detected by a triple-quadrupole tandem mass spectrometer,and electrospray and multiple reaction monitoring（MRM） were employed to select LTZ at m/z 286.4/217.1 and IS at m/z 294.1/225.3 simultaneously in the positive ion mode.The calibration curve showed good linearity ranging from 0.8–2000.0 ng/mL（r〉0.99）.The intra-day and inter-day precisions of LTZ were 4.0%–8.4%,with an accuracy of 98.6%–104.9%.Using this method,we successfully characterized the pharmacokinetics（PK） of LTZ by a one-compartment model with first-order absorption in female BALB/c nude mice.展开更多
Breast cancer is the second leading cause of cancer death in women mainly due to metastasis,which is closely related to cancer stemness.Evidence has shown that cancer stem-like cells(CSCs),which are responsible for ca...Breast cancer is the second leading cause of cancer death in women mainly due to metastasis,which is closely related to cancer stemness.Evidence has shown that cancer stem-like cells(CSCs),which are responsible for cancer stemness,can be decreased by activating dopamine D1 receptor(D1 DR).In the present study,we aimed to explore the pharmacological effects as well as the underlying mechanisms of QAP21,a newly synthesized compound that can be orally administered,in metastatic breast cancer cells.Our results showed that QAP21 dose-dependently inhibited the ability of colony formation in 4 T1 and MDA-MB-231 cells.Cell mobility,including cell migration and invasion,was also remarkably inhibited.Besides,QAP21 significantly inhibited mammosphere formation and decreased CSC proportion,indicating reduced cancer stemness.We further verified that the nuclear factor-kappa B(NF-κB)/Akt/epithelial-mesenchymal transition(EMT)pathway was markedly impacted by QAP21 treatment.Moreover,QAP21 up-regulated the expressions of D1 DR and its second messengers,including cAMP and cGMP,which can be increased when D1 DR is activated.SCH 23390,a specific D1 DR antagonist,partially or completely reversed the above-mentioned effects of QAP21,indicating that D1 DR activation might be involved in the underlying mechanism of QAP21.In summary,QAP21 effectively reduced breast cancer stemness and cell mobility,indicating its potential use for metastatic breast cancer therapy.展开更多
Sunitinib(SUN)is a multi-targeted receptor tyrosine kinase inhibitor(TKI)that may lead to drug resistance and metastasis because of increased cancer stem-like cells(CSCs)due to the induction of hypoxia.Our group has p...Sunitinib(SUN)is a multi-targeted receptor tyrosine kinase inhibitor(TKI)that may lead to drug resistance and metastasis because of increased cancer stem-like cells(CSCs)due to the induction of hypoxia.Our group has proved that dopamine(DA)can specifically reduce CSC frequency and enhance the response of SUN in drug-resistant breast cancerand non-small cell lung cancer(NSCLC).In this study,DA and SUN combination therapy was investigated in the treatment of pancreatic cancer,a malignant tumor with high mortality rate and very limited therapies.The cytotoxicity assay,clone formation assay and wound healing assay in two pancreatic cancer cell line PANC-1 and SW1990 showed that DA could significantly increase the effect of SUN on cell survival,clone formation ability and migration ability.Besides,SW1990 cell-derived xenograft model and a pancreatic cancer patient-derived xenograft(PDX)model were constructed,further proving that DA could increase the in vivo anti-tumor efficacy of SUN,and could be reversed by SCH23390,a D1 dopamine receptor(D1DR)antagonist.Moreover,the CSC frequency of the combination groups was lower than the control groups or SUN monotherapy groups.In addition,the body weight,H&E staining and blood routine test results showed that the combination therapy was safe.In summary,DA and SUN combination therapy could be a promising strategy for the treatment of pancreatic cancer.展开更多
基金National Natural Science Foundation of China(NSFC,Grant No.81673500)
文摘In the current study, we established and validated a simple and sensitive liquid chromatography-tandem mass spectrometric method for the determination of 21-hydroxy deflazacort in nude mice plasma, and such a method was applied to a pharmacokinetic study. Using betamethasone as the internal standard, the plasma samples were pre-treated by precipitation with acetonitrile and then analyzed on a reversed-phase C18 column （50 mm×2 mm, 5 μm） with a mobile phase consisting of acetonitrile and 4.0 mM ammonium formate （pH was adjusted to 3.5 with formic acid （40：60, v/v））. The analyte was detected by a triple quadrupole tandem mass spectrometer using electrospray, and multiple reaction monitoring was employed to select 21-hydroxy deflazacort at m/z 400.2/124.0 and betamethasone at m/z 393.3/147.0 in the positive ion mode. The calibration curves were linear （r〉0.99） over the range of 0.5~,00 ng/mL. The intra- and inter-day precisions and accuracies were 4.5%-10.1% and -1.7%-10.7% respectively. This method was successfully applied to a preclinical administered with a single oral dose of 4 mg/kg deflazacort, and its pharmacokinetic study of deflazacort on female nude mice pharmacokinetics was characterized by a two-compartment model with first-order absorption.
基金National Natural Science Foundation of China(Grant No.81673500)Innovation Team of Ministry of Education(Grant No.BMU2017TD003)
文摘A sensitive,rapid and simple liquid chromatography-tandem mass spectrometric（LC-MS/MS） method was developed and validated for the determination of letrozole（LTZ） in nude mouse plasma in the current study,which was successfully applied to a pharmacokinetic study.Using anastrozole as internal standard（IS）,plasma samples went through a one-step protein precipitation with acetonitrile before determination.The analyte and IS were analyzed on a reversed-phase ZORBAX-SB-C18 column（4.6 mm×250 mm,5 μm） with an isocratic mobile phase consisting of acetonitrile and water containing 0.1% formic acid（v/v） at a flow rate of 1.0 mL/min.The analyte and IS were detected by a triple-quadrupole tandem mass spectrometer,and electrospray and multiple reaction monitoring（MRM） were employed to select LTZ at m/z 286.4/217.1 and IS at m/z 294.1/225.3 simultaneously in the positive ion mode.The calibration curve showed good linearity ranging from 0.8–2000.0 ng/mL（r〉0.99）.The intra-day and inter-day precisions of LTZ were 4.0%–8.4%,with an accuracy of 98.6%–104.9%.Using this method,we successfully characterized the pharmacokinetics（PK） of LTZ by a one-compartment model with first-order absorption in female BALB/c nude mice.
基金Beijing Municipal Natural Science Foundation(Grant No.7192100)Innovation Team of Ministry of Education(Grant No.BMU2017TD003)。
文摘Breast cancer is the second leading cause of cancer death in women mainly due to metastasis,which is closely related to cancer stemness.Evidence has shown that cancer stem-like cells(CSCs),which are responsible for cancer stemness,can be decreased by activating dopamine D1 receptor(D1 DR).In the present study,we aimed to explore the pharmacological effects as well as the underlying mechanisms of QAP21,a newly synthesized compound that can be orally administered,in metastatic breast cancer cells.Our results showed that QAP21 dose-dependently inhibited the ability of colony formation in 4 T1 and MDA-MB-231 cells.Cell mobility,including cell migration and invasion,was also remarkably inhibited.Besides,QAP21 significantly inhibited mammosphere formation and decreased CSC proportion,indicating reduced cancer stemness.We further verified that the nuclear factor-kappa B(NF-κB)/Akt/epithelial-mesenchymal transition(EMT)pathway was markedly impacted by QAP21 treatment.Moreover,QAP21 up-regulated the expressions of D1 DR and its second messengers,including cAMP and cGMP,which can be increased when D1 DR is activated.SCH 23390,a specific D1 DR antagonist,partially or completely reversed the above-mentioned effects of QAP21,indicating that D1 DR activation might be involved in the underlying mechanism of QAP21.In summary,QAP21 effectively reduced breast cancer stemness and cell mobility,indicating its potential use for metastatic breast cancer therapy.
基金National Natural Science Foundation of China(Grant No.81473277)Innovation Team of Ministry of Education(Grant No.BMU2017TD003)。
文摘Sunitinib(SUN)is a multi-targeted receptor tyrosine kinase inhibitor(TKI)that may lead to drug resistance and metastasis because of increased cancer stem-like cells(CSCs)due to the induction of hypoxia.Our group has proved that dopamine(DA)can specifically reduce CSC frequency and enhance the response of SUN in drug-resistant breast cancerand non-small cell lung cancer(NSCLC).In this study,DA and SUN combination therapy was investigated in the treatment of pancreatic cancer,a malignant tumor with high mortality rate and very limited therapies.The cytotoxicity assay,clone formation assay and wound healing assay in two pancreatic cancer cell line PANC-1 and SW1990 showed that DA could significantly increase the effect of SUN on cell survival,clone formation ability and migration ability.Besides,SW1990 cell-derived xenograft model and a pancreatic cancer patient-derived xenograft(PDX)model were constructed,further proving that DA could increase the in vivo anti-tumor efficacy of SUN,and could be reversed by SCH23390,a D1 dopamine receptor(D1DR)antagonist.Moreover,the CSC frequency of the combination groups was lower than the control groups or SUN monotherapy groups.In addition,the body weight,H&E staining and blood routine test results showed that the combination therapy was safe.In summary,DA and SUN combination therapy could be a promising strategy for the treatment of pancreatic cancer.
